Background and Hypothesis Zinc finger protein 804A (ZNF804A) was the first genome-wide associated susceptibility gene for schizophrenia (SCZ) and played an essential role in the pathophysiology of SCZ by influencing neurodevelopment regulation, neurite outgrowth, synaptic plasticity, and RNA translational control; however, the exact molecular mechanism remains unclear. Study Design A nervous-system-specific Zfp804a (ZNF804A murine gene) conditional knockout (cKO) mouse model was generated using clustered regularly interspaced short palindromic repeat/Cas9 technology and the Cre/loxP method. Results Multiple and complex SCZ-like behaviors, such as anxiety, depression, and impaired cognition, were observed in Zfp804a cKO mice. Molecular biological methods and targeted metabolomics assay validated that Zfp804a cKO mice displayed altered SATB2 (a cortical superficial neuron marker) expression in the cortex; aberrant NeuN, cleaved caspase 3, and DLG4 (markers of mature neurons, apoptosis, and postsynapse, respectively) expressions in the hippocampus and a loss of glutamate (Glu)/γ-aminobutyric acid (GABA) homeostasis with abnormal GAD67 (Gad1) expression in the hippocampus. Clozapine partly ameliorated some SCZ-like behaviors, reversed the disequilibrium of the Glu/GABA ratio, and recovered the expression of GAD67 in cKO mice. Conclusions Zfp804a cKO mice reproducing SCZ-like pathological and behavioral phenotypes were successfully developed. A novel mechanism was determined in which Zfp804a caused Glu/GABA imbalance and reduced GAD67 expression, which was partly recovered by clozapine treatment. These findings underscore the role of altered gene expression in understanding the pathogenesis of SCZ and provide a reliable SCZ model for future therapeutic interventions and biomarker discovery.

中文翻译：

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zfp804a 条件性敲除小鼠的精神分裂症样缺陷和谷氨酸/γ-氨基丁酸稳态受损


背景和假设锌指蛋白 804A （ZNF804A） 是精神分裂症 （SCZ） 的第一个全基因组相关易感基因，通过影响神经发育调节、神经突生长、突触可塑性和 RNA 翻译控制在 SCZ 的病理生理学中发挥重要作用;然而，确切的分子机制仍不清楚。研究设计 使用成簇规则间隔短回文重复序列/Cas9 技术和 Cre/loxP 方法生成神经系统特异性 Zfp804a （ZNF804A 小鼠基因） 条件敲除 （cKO） 小鼠模型。结果 在 Zfp804a cKO 小鼠中观察到多种复杂的 SCZ 样行为，如焦虑、抑郁和认知障碍。分子生物学方法和靶向代谢组学测定证实 Zfp804a cKO 小鼠在皮层中表现出改变的 SATB2 （一种皮层浅表神经元标志物） 表达;海马中异常的 NeuN、裂解的 caspase 3 和 DLG4 （分别为成熟神经元、细胞凋亡和突触后的标志物） 表达以及海马中谷氨酸 （Glu）/γ-氨基丁酸 （GABA） 稳态的缺失和 GAD67 （Gad1） 表达异常。氯氮平部分改善了一些 SCZ 样行为，逆转了 Glu/GABA 比率的不平衡，并恢复了 cKO 小鼠中 GAD67 的表达。结论 成功培养了再现 SCZ 样病理和行为表型的 Zfp804a cKO 小鼠。确定了 Zfp804a 导致 Glu/GABA 失衡并降低 GAD67 表达的新机制，氯氮平治疗部分恢复了 GAD67 表达。 这些发现强调了基因表达改变在理解 SCZ 发病机制中的作用，并为未来的治疗干预和生物标志物发现提供了可靠的 SCZ 模型。